The central goal of this R21 proposal is to understand how Staphylococcus aureus subverts syndecan-1, a major cell surface heparan sulfate proteoglycan (HSPG), to promote its pathogenesis in the lung. Host-pathogen interactions largely dictate the onset, progression, and outcome of infectious diseases. Many bacteria bind to cell surface HSPGs in vitro, and this activity is thought to be critical in the initial attachment to host cells in vivo. To determine the physiological significance of HSPG-pathogen interactions in vivo, we examined the role of syndecan-1 in a mouse model of S. aureus pneumonia. S. aureus pneumonia is a common complication among ventilated patients, and also a serious problem in patients at the extremes of ages with predisposing diseases, patients with immunosuppressive therapy or illness, and in individuals with cystic fibrosis. Preliminary studies showed that S. aureus virulence is significantly attenuated in the lungs of syndecan-1 null mice compared to those of wild type mice. However, unexpectedly, S. aureus did not bind to syndecan-1 and S. aureus adhesion to lung epithelial cells was not dependent on syndecan-1. These data suggested that S. aureus exploits syndecan-1 for its pathogenesis, but not as a cell surface receptor that facilitates its initial attachment to host cells. Instead, preliminary studies showed that a secreted soluble form of syndecan-1 promotes S. aureus pneumonia in a heparan sulfate-dependent manner. Based on these data, we will explore how syndecan-1 functions as a pro-pathogenic factor in S. aureus pneumonia in two specific aims. In Aim 1, we will explore the hypothesis that syndecan-1 ectodomain promotes S. aureus pneumonia by inhibiting neutrophil-mediated host defense mechanisms and the staphylocidal activity of soluble defense factors in the airway. In Aim 2, we will explore the hypothesis that the induction of syndecan-1 shedding is a critical virulence activity in the pathogenesis of S. aureus pneumonia. Through these studies, our goal is to gain new mechanistic insights that will facilitate future development of novel therapeutic approaches to attenuate, halt, or reverse disease progression in S. aureus pneumonia - a significant cause of mortality and morbidity. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus pneumonia is a significant cause of mortality and morbidity in the US and worldwide. This grant proposal will explore the underlying biological mechanisms of how Staphylococcus aureus promotes its survival in the lung and causes pneumonia by exploiting one of our own molecules called syndecan-1.